For the production of sterilized, bacteria-free and apyrogenic water, such as is required for injection and infusion solutions, it has been proposed that the so-called reverse osmosis or hyperfiltration may be used.
Reverse osmosis using semipermeable membranes has been employed in which water of low salt content is separated from a salt-containing water. If such a membrane is subjected to a salt containing water under a pressure exceeding the osmotic pressure of the solution, water of low salt content passes through and germs or bacteria and pyrogens are also retained by the membrane.
Reverse osmosis can be used to remove germs, bacteria and pyrogens from water which has previously been deionized by any conventional means.
Membranes which have been used for this purpose have been formed of acetyl celluloses, polyamides or polyolefins. Water transportation through the membranes is impeded by the concentration or polarization that occurs of retained substances. By a suitable excess flow oriented tangentially to the surface, such concentration and polarization can be reduced and the membrane surface can be largely kept clear of microscopic and larger bodies such as germs, bacteria and pyrogens.
The disadvantage of the known processes and apparatus comprising the semipermeable membranes is, however, that the membranes must be continually subjected to the action of water, in order that the semipermeable membranes are not damaged by bacteria which are unable to pass through the membranes. If the installation is shut down and no water flow takes place over the membrane, colonies of bacteria can form which attack the membrane, so that when operation is resumed germs will pass through the fairly large holes which are now present. On the other hand, a requirement for such pure water usually does not exist continuously, or the requirement for pure water is highly fluctuating, so that a solution must be found for collecting and storing the sterile permeate under sterile conditions.
Storage of the sterile permeate has normally been done in containers maintained under sterile conditions with the permeate in the containers at an elevated temperature, preferably 85.degree. C., while it is stored. Such storage is not particularly economical. The provision of storage vessels for the sterilized permeate incurs capital costs and also the vessels occupy valuable space. Additionally, the vessels must be kept sterile. The energy consumption is considerable both for heating and maintaining the temperature at 85.degree. C. and also for cooling the permeate when required for the intended purposes.
A further disadvantage is that, due to the particular nature of the above-described process of reverse osmosis, a considerable proportion of the water supplied to the semipermeable membrane serves only as excess water for maintaining at the surface of the membrane a flow of water for the above-mentioned reasons.
Systems in which a portion of the deionized water which is supplied to the reverse osmosis filter or membrane has been recycled to maintain the membrane as free as possible of bacteria and pyrogens which have been retained on the filter to minimize the possibility of bacteria attack on the filter are disclosed, for example, in French Pat. No. 2,207,868 and Marquardt, K., Moderne Wasseraufbereitung in zentralen Dialysestationen durch Umkehrosmose-Anlagen, Hager and Elsasser GmbH, Stuttgart, Heft 4/76. In addition, the latter cited German publication also discloses a system in which sterile permeate may be recycled to eliminate the need for storage vessels and their attendant disadvantages during periods of low sterile permeate demand.
Although the last mentioned systems have solved some of the problems which exist in the removal of bacteria using reverse osmosis filters or membranes, they have not successfully solved all of the problems that must be overcome in order for such membrane systems to be fully accepted for the preparation of water which is of sufficient purity for use in the injection of medicinals into the human body. Although such reverse osmosis filters or membranes have been accepted by the United States Pharmacopoeia for the preparation of pyrogen-free water for injection, they have not been accepted for the preparation of bacteria-free water for this purpose. Goodall, J., Process Water Purification; RO Techniques and Economics, Proceedings of the Filtration Society, 1977, p. 652.
The present inventor has discovered that even though recycling of a portion of the deionized water removes substantial amounts of bacteria from the filter surfaces and reduces the likelihood of attack on the membrane, some bacteria still remains which will attack the membrane and eventually a certain amount of bacteria will enter the permeate at these points of attack. Moreover, in the prior systems it has been generally necessary to recycle a substantial amount of the deionized water to insure that a sufficient flushing action occurs at the membrane surface to delay for as long as possible attack of the membrane by the bacteria. Such substantial recycling of the deionized water is not only wasteful of pumping energy, but also results in reduced system capacity and increased cooling requirements to cool the recycled water which is heated by the pumping energy necessitated by such recycling.
The inventor has also discovered that where sterilizing fluids have been periodically employed to flush the prior systems, that the membranes of these systems were not of sufficient configuration to enable the sterilant to reach all portions of the membrane surfaces. Thus, the membranes were subjected to attack by bacteria on those portions of their surfaces which could not be reached by the sterilizing fluid and bacteria escaped into the permeate.
The process and apparatus incorporating the principles of the present invention is capable of producing a consistently sterile, bacteria and pyrogen-free permeate suitable for medicinal injections and other purposes contrary to the aforementioned Goodall publication and overcome all of the aforementioned disadvantages of the prior systems. The process and apparatus incorporating the principles of the present invention achieves this result while at the same time minimizing energy and capital requirements and maximizing capacity.
In one principal aspect of the present invention, a process for producing sterilized water free of bacteria and pyrogens and suitable for medicinal injection includes the step of circulating deionized water into contact with a reverse osmosis-filter formed of a material which is substantially impervious to attack by bacteria in the water. A portion of the deionized water is passed through the filter to obtain a sterile permeate and another portion is recycled from the filter. The sterile permeate which is not used is also recycled to the filter. At least periodically all portions of the surface of the filter are sterilized with a sterilizing fluid.
In another principal aspect of the present invention, apparatus for producing sterilized water free of bacteria and pyrogens and suitable for medicinal injection comprises a source of deionized water, a reverse osmosis filter formed of a material which is substantially impervious to attack by bacteria in the water, means for supplying the deionized water from the source to and into contact with the filter and passing a portion of the deionized water through the filter to obtain a sterile permeate. The apparatus also includes means for recycling another portion of the water which is not passed through the filter from the filter and means removes the sterile permeate from the filter withdraws the permeate for use and recycles the remainder of the permeate to the filter. Means at least periodically supplies a sterilizing fluid to the filter and the filter is constructed and arranged such that all portions of its surface are exposed to the sterilizing fluid.
In another principal aspect of the present invention, the filter which is impervious to bacteria attack is formed of a fluorine substituted polymer.
In still another principal aspect of the present invention, the filter is arranged in coil or plate form to enable the sterilizing fluid to reach all portions of the surface thereof.
These and other objects, features and advantages of the present invention will become apparent when considering the following detailed description of a preferred embodiment.